In 1942 Albright and his associates described the features of a new clinical syndrome "pseudohypoparathyroidism" (PHP). Patients with this disorder differ from those with idiopathic hypoparathyroidism: they show characteristic constitutional features (Albright's hereditary osteodystrophy - AHO) and do not respond to exogenous parathyroid hormone (PTH). Subsequent to the original report, patients lacking the typical somatic features of AHO but resistant to endogenous and administered PTH have been described. In PHP, UcAMP (urinary cyclic AMP) does not increase normally in response to PTH administration. This indicated that there is a defective hormone receptor-adenylate cyclase complex in this disorder. We have now shown that many patients with PHP+AHO (PHP Ia) show an approximately 50% reduction in activity of Gs (the stimulatory guanine nucleotide binding protein associated with adenylate cyclase) in membranes from multiple tissues. Gs deficiency presumably accounts for resistance to multiple hormones in such patients. Patients with PHP without AHO show normal Gs activity (PHP Ib) and resistance only to PTH, and preliminary studies suggest a PTH receptor defect in such patients. Rare patients with PHP and AHO and multiple hormone resistance show normal Gs activity. Using cloned human cDNA probes for the alpha subunit of Gs, we now find that steady state mRNA levels from fibroblasts of subjects with PHP Ia are reduced by approximately 50% compared with normals. Genomic blotting and other molecular biologic approaches are being used to define the genetic abnormality responsible for Gs deficiency in PHP Ia.